Glutamine supports cell survival, growth and proliferation of cancer cells through metabolic and non-metabolic mechanisms. In actively proliferating cells, the metabolism of glutamine is a major source of building blocks and energy for the cells. When glutamine is withdrawn from the media in which the cancer cells are grown, the cells frequently stop growing or die. In cancer cells, much of the glutamine that is taken up by the cells is converted to glutamate through the action of the enzyme glutaminase. Thus, conversion of glutamine to glutamate via glutaminase is a control point for glutamine metabolism.
Ever since Warburg's observation that ascites tumor cells exhibited high rates of glucose consumption and lactate secretion in the presence of oxygen, researchers have been exploring how cancer cells utilize metabolic pathways to be able to continue actively proliferating. Several reports have demonstrated how glutamine metabolism supports macromolecular synthesis necessary for cells to replicate.
Thus, glutaminase has been theorized to be a potential therapeutic target for the treatment of diseases characterized by actively proliferating cells, such as cancer. The lack of suitable glutaminase inhibitors with good pharmaceutical properties has made it difficult to develop glutaminase inhibitors for clinical use. Therefore, the creation of glutaminase inhibitors that are specific and capable of being formulated for in vivo use could lead to a new class of therapeutics. Specifically, what is needed are improved compositions and methods for preparing and formulating glutaminase inhibitors.